Neuroscience
-
The synthetic retinoid 13-cis-retinoic acid (13-cis-RA), prescribed for the treatment of severe nodular acne, has been linked to an increased incidence of depression. Chronic treatment studies in rodents have shown that 13-cis-RA induces an increase in depression-related behaviours and a functional uncoupling of the hippocampus and dorsal raphe nucleus (DRN). Changes in the number of serotoninergic neurons in the DRN have been reported in depressed human patients. ⋯ Similarly, changes in the density of serotoninergic neurons or in the volume of the MRN or DRN were not observed in 13-cis-RA treated animals. These data show that apoptotic actions of 13-cis-RA do not occur in vivo at drug concentrations that induce changes in depression-related behaviour and functional uncoupling of the DRN and hippocampus. The potential pro-depressant behavioural and molecular effects associated with chronic administration of 13-cis-RA may result from changes in serotoninergic activity rather than changes in the number of serotoninergic neurons.
-
In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab [Wehrwein E, Thompson SA, Coulibaly SF, Linn DM, Linn CL (2004) Invest Ophthalmol Vis Sci 45:1531-1543] have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes [Asomugha CO, Linn DM, Linn CL (2010) J Neurochem 112:214-226]. ⋯ In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before an excitotoxic insult leads to neuroprotection. In the future, these results could provide important information concerning therapeutic agents developed to combat various diseases involved with glutamate-induced excitotoxicity.
-
The cerebellum, which controls coordinated and rapid movements, is a potential target for the deleterious effects of drugs of abuse including cannabis (i.e. marijuana, cannabinoids). Prenatal exposure to cannabinoids has been documented to cause abnormalities in motor and cognitive development, but the exact mechanism of this effect at the cellular level has not been fully elucidated. Previous studies indicate that cannabinoids are capable of modulating synaptic neurotransmission. ⋯ WIN treatment of pregnant rats also profoundly affected the intrinsic properties of Purkinje neurons in offspring. This treatment increased the firing regularity, firing frequency, amplitude of afterhyperpolarization (AHP), the peak amplitude of action potential and the first spike latency, but decreased significantly the time to peak and duration of action potentials, the instantaneous firing frequency, the rate of rebound action potential and the voltage "sag" ratio. These results raise the possibility that maternal exposure to cannabinoids may profoundly affect the intrinsic membrane properties of cerebellar Purkinje neurons of offspring by altering the membrane excitability through modulation of intrinsic ion channels.
-
Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1, KIAA0319, and DCDC2. Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these genes dramatically disrupts neuronal migration to the cerebral cortex by both cell autonomous and non-cell autonomous effects. Here we sought to investigate the extent of non-cell autonomous effects following in utero disruption of the candidate dyslexia susceptibility gene homolog Dyx1c1 by assessing the effects of this disruption on GABAergic neurons. ⋯ We found untransfected GABAergic neurons (parvalbumin, calretinin, and neuropeptide Y) in the heterotopic collections of neurons in Dyx1c1 shRNA treated animals, supporting the hypothesis of non-cell autonomous effects. In contrast, we found no evidence that the position of the GABAergic neurons that made it to the cerebral cortex was disrupted by the embryonic transfection with any of the constructs. Taken together, these results support the notion that neurons within heterotopias caused by transfection with Dyx1c1 shRNA result from both cell autonomous and non-cell autonomous effects, but there is no evidence to support non-cell autonomous disruption of neuronal position in the cerebral cortex itself.
-
Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input. ⋯ Administration of slow-release pellets containing 17β-estradiol at week 5 post OVX reversed both the development of the hyperalgesia and the enhanced activation of ERK 1/2, suggesting that this activation, like the hyperalgesic state, was estrogen-dependent. Intrathecal injections of the ERK 1/2 inhibitor U0126 successfully rescued the mice from the abdominal hyperalgesia for up to 24 h after the injection and also reversed the enhanced expression of ERK 1/2. Our study shows, for the first time, activation of ERK 1/2 in the spinal cord matching the time course of an estrogen-dependent chronic hyperalgesic state.